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J. Biol. Chem., Vol. 279, Issue 39, 40328-40336, September 24, 2004

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Inhibition of Mitochondrial Na⁺-Ca²+ Exchange Restores Agonist-induced ATP Production and Ca²+ Handling in Human Complex I Deficiency^*

Henk-Jan Visch¶||, Guy A. Rutter**, Werner J. H. Koopman¶, Jan B. Koenderink¶, Sjoerd Verkaart¶||, Theun de Groot¶, Aniko Varadi**, Kathryn J. Mitchell**, Lambert P. van den Heuvel||, Jan A. M. Smeitink||¶¶, and Peter H. G. M. Willems¶

From the Departments of Biochemistry and Pediatrics and the Microscopical Imaging Center, Nijmegen Centers of ^¶Molecular Life Sciences and ^||Mitochondrial Disorders, University Medical Center Nijmegen, NL-6500 HB Nijmegen, The Netherlands and the ^**Henry Wellcome Signalling Laboratories and Department of Biochemistry, University of Bristol, BS8 1TD Bristol, United Kingdom

Human mitochondrial complex I (NADH:ubiquinone oxidoreductase) of the oxidative phosphorylation system is a multiprotein assembly comprising both nuclear and mitochondrially encoded subunits. Deficiency of this complex is associated with numerous clinical syndromes ranging from highly progressive, often early lethal encephalopathies, of which Leigh disease is the most frequent, to neurodegenerative disorders in adult life, including Leber's hereditary optic neuropathy and Parkinson disease. We show here that the cytosolic Ca²⁺ signal in response to hormonal stimulation with bradykinin was impaired in skin fibroblasts from children between the ages of 0 and 5 years with an isolated complex I deficiency caused by mutations in nuclear encoded structural subunits of the complex. Inhibition of mitochondrial Na⁺-Ca²⁺ exchange by the benzothiazepine CGP37157completely restored the aberrant cytosolic Ca²⁺ signal. This effect of the inhibitor was paralleled by complete restoration of the bradykinin-induced increases in mitochondrial Ca²⁺ concentration and ensuing ATP production. Thus, impaired mitochondrial Ca²⁺ accumulation during agonist stimulation is a major consequence of human complex I deficiency, a finding that may provide the basis for the development of new therapeutic approaches to this disorder.

Received for publication, July 16, 2004

^* This work was supported by 6th Framework Programma Integrated Project Grant LSHM-CT-2004-503116 from the European Community and a Van Walree Fund grant from the Royal Netherlands Academy of Arts and Sciences. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Wellcome Trust Research Leave Fellowship and Programme Grant 067081/Z/02/Z, the Human Frontiers Science Program, the Medical Research Council (United Kingdom), and Diabetes UK.

^¶¶ To whom correspondence should be addressed: Nijmegen Center for Mitochondrial Disorders, Dept. of Pediatrics, University Medical Center Nijmegen, P. O. Box 9101, NL-6500 HB Nijmegen, The Netherlands. Tel.: 31-243614430; Fax: 31-243616428; E-mail: j.smeitink{at}cukz.umcn.nl.

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